The present invention relates to a process for preparing doxazosin mesylate in a crystal modification referred to as form A, and to an intermediate through which this process proceeds.
Doxazosin (=4-amino-2-[4-(1,4-benzodioxane-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquinazoline) is a known substance (Merck Index, 12th Edition, 1996, No. 3489) which lowers blood pressure. The substance is mainly used in the form of the monomesylate which, in crystalline form, according to the statements in the Chinese Journal of Medicinal Chemistry 5(4), 266-270 (1995), at present occurs in 3 crystal modifications. The various modifications are referred to as modifications A, B and C in said citation. Modification A is obtained on recrystallization of doxazosin mesylate from ethanol. Modifications B and C result on recrystallization of doxazosin mesylate from chloroform and water respectively. Mention may be made of the fact that the Chinese Journal of Medicinal Chemistry in fact speaks only of doxazosin. However, according to the published data, the material must be doxazosin mesylate.
Although doxazosin is mostly used as monomesylate, the preparation of this salt has not to date been described. Concerning the known modifications of doxazosin mesylate, it has emerged that the mesylate does not dissolve even in 75 times the amount of chloroform at the boiling point. The product isolated after cooling the suspension contains chloroform, which is a solvent which is objectionable from the toxicological viewpoint and which can be removed only with difficulty and not without adverse effects on the active ingredient. Although the mesylate dissolves better in water, the product which results on cooling this solution can be isolated only with difficulty. In addition, the yield is poor and the material proves to be X-ray amorphous. The mesylate does not dissolve even in 350 times the amount of ethanol at the boiling point of the solvent. Hot filtration of the suspension affords a small yield of the described ethanol modification A as residue on the filter. Cooling the filtrate results in only a moderate yield of impure A modification.
Thus, not only has the preparation of doxazosin mesylate not to date been described, there is also no method which can be used on the industrial scale to obtain a particular modification of doxazosin mesylate. Of the described modifications, because of the properties indicated above, modifications B and C are unsuitable for developing a process. Only modification A is suitable for this on the basis of its properties.
A process which can be used on the industrial scale to prepare doxazosin mesylate in crystal modification A has now been found.
The present invention relates to a process for preparing doxazosin mesylate in modification A which comprises dissolving doxazosin with methanesulfonic acid in methanol, removing any turbidity from the resulting solution, and stirring the resulting clear solution until no further precipitate separates out, removing, washing with methanol, heating the precipitate in the moist state in ethanol and, after cooling, isolating the resulting product.
For the reaction of doxazosin with methanesulfonic acid, the two substances are employed in the molar ratio of about 1:1. A small molar excess of the sulfonic acid is preferably used (up to about 10%).
If the time between obtaining a solution by adding methanesulfonic acid to doxazosin and the appearance of a precipitate is insufficient for a filtrationxe2x80x94for example if the reaction is to be carried out on the industrial scalexe2x80x94the time for the filtration can be extended by adding an aprotic, polar organic solvent to the methanol used for the reaction.
Examples of suitable aprotic, polar organic solvents in this case are N,N-dimethylformamide and, in particular, N-methyl-2-pyrrolidone. The ratio of doxazosin to methanol (weight/volume) or the ratio of doxazosin to methanol to the aprotic, polar organic solvent (weight/volume/volume) is about 1:(5 to 15), preferably about 1:(8 to 12) or about 1:(5 to 15):(1.5 to 4), preferably about 1:(8 to 12):(2 to 3).
If in the novel process any foreign particles present in the solution obtained after adding methanesulfonic acid are to be removed by filtration it is preferable to use a solvent mixture of aprotic, polar organic solvent and methanol in the first reaction stage. The reason is that in this case, as already mentioned, the time between obtaining the solution and the first crystal formation is greater than on use of methanol alone as solvent. If filtration of the solution obtained after adding methanesulfonic acid is desired in the first reaction stage of the novel process, a particularly preferred procedure is to use the solvent mixture with aprotic, polar organic solvent and moreover to add part of the methanol only after the filtration.
The precipitate resulting after the mixing of doxazosin and methanesulfonic acid represents a novel modification of doxazosin mesylate, which is referred to as modification D herein. The present invention likewise relates to this modification. It is characterized in particular by principal lines in the Debye-Scherrer X-ray diffractogram at the following values of 2 theta which are indicated in degrees of angle: 5.72xc2x10.2xc2x0, 11.10xc2x10.2xc2x0, 11.46xc2x10.2xc2x0, 14.14xc2x10.2xc2x0, 17.01xc2x10.2xc2x0, 17.78xc2x10.2xc2x0, 18.33xc2x10.2xc2x0, 20.73xc2x10.2xc2x0, 21.70xc2x10.2xc2x0, 23.12xc2x10.2xc2x0, 24.28xc2x10.2xc2x0, 26.58xc2x10.2xc2x0.
After its removal, doxazosin mesylate (modification D) is washed with methanol, and the product moist with solvent (moisture content about 10-60%, preferably 25-50%) is further processed to modification A of doxazosin mesylate.
Conversion of moist modification D takes place in a simple manner by heating in ethanol. This preferably entails heating under reflux. The amount of ethanol used should be such that a suspension is always present during the conversion. It preferably amounts to about ten times the amount of moist modification D employed, based on its dry weight, i.e. 100 ml of ethanol are used for 10 g of dry substance.
The novel process affords doxazosin mesylate in modification A in an overall yield of more than 85%. The purity of the modification A obtained by the novel process is excellent. Another considerable advantage of the novel process is that a solution is produced after addition of the methanesulfonic acid to the doxazosin. This makes it possible to remove any foreign particles present by filtration.